1. Field of the Invention
This invention relates to the use of peptide hormone analogues useful in inhibiting the naturally occurring hormone peptide in vivo and in vitro. These peptide hormone analogues when administered to a vertebrate, such as mammals, fish or birds, block the endrocrine activity of the peptide hormone or other analogous molecules. These peptide hormone analogues are also useful in vitro in combination with a bioassay for the naturally occurring hormone. These peptide hormone analogues are useful in treating various diseases caused by hormone excess and in treating hormone dependent tumors. One example of this invention relates to the synthesis of parathyroid hormone analogues useful in inhibiting the action of parathyroid hormone both in vivo and in vitro.
2. Description of the Prior Art
Analysis of the relation of structure to hormonal function has provided important insights into the mechanism of action of peptide hormones. Each type of peptide hormone has an affinity for specific receptors to which it binds. Upon binding, the peptide hormone acts either directly or causes a change in the intracellular concentration of a second messenger molecule such as cyclic AMP, cyclic GMP, or calcium ions. These second messenger molecules, in turn, cause changes in the metabolism or physiology of the cell. These changes in cell metabolism or physiology are therefore directly or indirectly dependent upon the binding of the peptide hormone to its specific cell surface receptor. Therefore, if the cell surface receptor is blocked then the hormone effect is also blocked.
Peptide hormone analogues have long been known as a method through which the biochemistry of hormones can be studied and evaluated. Endocrinologists have long desired a method for producing a class of peptide hormone analogues which would allow the blocking of specific hormone receptors without activating a change in the second messenger molecules, thereby avoiding the hormone induced metabolic changes.
The following publications described the structure of peptide hormone analogues and their binding to cell receptors. In particular, these publications describe the properties of parathyroid hormone analogues and their physiological properties: (1) M. Rosenblatt, American Society for Bone and Mineral Research, Abstract, 1982, in press; (2) G. V. Segre, et al., Calcified Tissue International, 28 (2): 171, 1979; (3) K. Martin, et al., Clinical Research, 28 (2): 398a, April 1980; (4) J. McGowan, et al., Central Society for Clinical Research, 1981; (5) M. Rosenblatt, et al., Journal of Biological Chemistry, 252 (16): 5847, 1977; (6) S. R. Goldring, et al., Journal of Clincal Endocrinology and Metabolism, 48 (4): 655, 1979; (7) G. V. Segre, et al., Journal of Biological Chemistry, 254 (15): 6980, 1979; (18) D. A. Ausiello, et al., American Journal of Physiology (published by The American Physiological Society) E144, 1980; (9) M. Rosenblatt, et al., Endrocrine Research Communications, 4 (2): 115, 1977; (10) M. Coltrera, et al., Biochemistry, 19, 4380, 1980; (11) J. E. Mahaffey, et al., The Journal of Biological Chemistry, 254 (14): 6496, 1979; (12) M. Rosenblatt, et al., Endocrinology, 107 (2): 545, 1980; (13) S. R. Nussbaum, et al., The Journal of Biological Chemistry, 255 (21): 10183, 1980; (14) M. Rosenblatt, et al., Calcified Tissue International, 33, 153, 1981; (15) M. Rosenblatt, et al., Biochemistry, 20, 7243, 1981; (16) M. Rosenblatt, et al., Pathobiology Annual, 11: 53, 1981. The preceding sixteen publications are hereby incorporated by reference.
The preceding articles describe the state of the art in parathyroid hormone analogue research. Scientific efforts over a period of many years have sought to understand the interaction between peptide hormones and the cell surface receptor specific for each peptide hormone. One of the peptide hormones, parathyroid hormone has been studied by using analogues of parathyroid hormone (PTH). One objective of these studies has been to understand the binding of the peptide hormone to the cell surface receptor such that an analogue could be constructed which would bind with the same or greater affinity than the naturally occurring hormone. This analogue would enable the peptide hormone analogue of parathyroid hormone to be used to block the effect of the naturally occurring parathyroid hormone. One of the major problems encountered in this search for a clinically and pharmacologically effective parathyroid hormone analogue was the problem of agonist activity. Agonist activity is the property of the peptide hormone analogue to itself stimulate the change in second messengers which brings about the physiological change associated with the naturally occurring hormone. Therefore, the problem was to create hormone analogues which would bind with high affinity to the appropriate hormone cell surface receptor but not stimulate a change in the second messenger concentration, that is, not act as hormone itself. These analogues could then be used in treating hormone related diseases.